Peripheral blood leukocytes (PBL) from asymptomatic, HIV-seropositive (HIV+) individuals exhibit a spectrum of T helper cell (Th) functional defects that is progressive and predictive for the onset of AIDS. These defects are reversed in patients who receive therapy with AZT, ddI, growth hormone, and recombinant CD4-IgG. The progression of these defects is seen "AIDS progressors", but not in "AIDS non-progressors" during a four-year follow-up. HIV-specific TH responses are detected in several groups of exposed, seronegative individuals, including homosexual men, IV drug abusers, newborns of HIV+ mothers, an accidentally-exposed health care workers. Many of these HIV Th-reative individuals have not seroconverted nor developed AIDS symptoms on follow-up, which raises the possibility of protective TH immunity. Such protective immunity may be associated with Thl cells, which produce IL-2 and, IFN-gamma, in contrast to Th2 cells, which produce IL-4 and IL-10, and which we found to be associated with progression to AIDS. Studies of patients with primary immune deficiencies exhibit defects in Th and APC function. Patients with Wiskott-Aldrich Syndrome exhibit a defect that involves an unstable immunogenic complex that is formed by self HLA class I, beta2-microglobulin and antigenic peptide.